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Cancer Research and Treatment > Volume 50(2); 2018 > Article
Liu, Wang, Zhang, Long, Zhang, Li, Chen, Li, Hua, Shen, and Peng: Declined Preoperative Aspartate Aminotransferase to Neutrophil Ratio Index Predicts Poor Prognosis in Patients with Intrahepatic Cholangiocarcinoma after Hepatectomy

Abstract

Purpose

Various inflammation-based prognostic biomarkers such as the platelet to lymphocyte ratio and neutrophil to lymphocyte ratio, are related to poor survival in patients with intrahepatic cholangiocarcinoma (ICC). This study aims to investigate the prognostic value of the aspartate aminotransferase to neutrophil ratio index (ANRI) in ICC after hepatic resection.

Materials and Methods

Data of 184 patients with ICC after hepatectomy were retrospectively reviewed. The cut-off value of ANRIwas determined by a receiver operating characteristic curve. Preoperative ANRI and clinicopathological variables were analyzed. The predictive value of preoperative ANRI for prognosis of ICC was identified by univariate and multivariate analyses.

Results

The optimal cut-off value of ANRI was 6.7. ANRI was associated with tumor size, tumor recurrence, white blood cell, neutrophil count, aspartate aminotransferase, and alanine transaminase. Univariate analysis showed that ANRI, sex, tumor number, tumor size, tumor differentiation, lymph node metastasis, resection margin, clinical TNM stage, neutrophil count, and carcinoembryonic antigen were markedly correlated with overall survival (OS) and disease-free survival (DFS) in patients with ICC. Multivariable analyses revealed that ANRI, a tumor size > 6 cm, poor tumor differentiation, and an R1 resection margin were independent prognostic factors for both OS and DFS. Additionally, preoperative ANRI also had a significant value to predict prognosis in various subgroups of ICC, including serum hepatitis B surface antigen‒negative and preoperative elevated carbohydrate antigen 19-9 patients.

Conclusion

Preoperative declined ANRI is a noninvasive, simple, and effective predictor of poor prognosis in patients with ICC after hepatectomy.

Introduction

Intrahepatic cholangiocarcinoma (ICC) is the second most common biliary malignancy and accounts for 5% to 10% of primary liver carcinomas [1]. A rapidly increasing incidence of ICC has been reported over the last few decades [2]. Operation is the only potentially curative therapeutic measure for patients with ICC. Unfortunately, less than 30% of ICC patients are not able to have an operation at the initial diagnosis due to a lack of appropriate markers for early diagnosis. In addition, even after curative hepatectomy, the outcome remains grim, with the 5-year survival rate ranging from 20% to 40% [3,4]. The poor prognosis after surgery is mainly due to tumor recurrence and metastasis [5]. Therefore, it is of great significance to screen for effective markers to identify ICC patients at a high risk of recurrence or metastases, thus providing timely and effective therapeutic treatment to improve the clinical outcomes.
As a routine liver function test index, aspartate aminotransferase (AST) reflects the damage of the liver. It is commonly used to assess the severity of various liver diseases [6]. Recently, studies have reported that prognostic indexes based on inflammatory cells such as neutrophils and lymphocytes can reflect the survival of various malignancies [7,8], with aspartate aminotransferase to neutrophil ratio index (ANRI) as one of them. For example, elevated ANRI was found to be significantly correlated with a poorer outcome in patients with hepatocellular carcinoma [9].
The relation between ANRI and the prognosis of ICC patients after hepatic resection has not been reported. In the present study, we aim to evaluate the predictive value of preoperative ANRI on both the overall survival (OS) and disease-free survival (DFS) of ICC patients after hepatectomy.

Materials and Methods

1. Patients

A total of 184 newly diagnosed ICC patients treated with hepatectomy at the First Affiliated Hospital, Sun Yat-sen University between April 2004 and September 2015 were included. All specimens were histologically proven to be ICC after surgery. Informed consent was obtained, and procedures were carried out with prior approval of the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University (Guangzhou, China). Routine assessment was performed for all patients within 7 days before surgery, including physical examination, complete hematologic and biochemistry profiles, chest X-ray, abdominal ultrasonography, and contrast-enhanced computed tomography (CT) scans or magnetic resonance imaging.
All patients were > 18 years of age, with complete clinical and laboratory data. No patients had any coexistent hematological disorders or known active infection before treatment. In addition, patients with preoperative anti-tumor treatment, such as chemotherapy or percutaneous ablation, were excluded from this study.

2. Treatment and follow-up

Surgical strategies were decided by a multidisciplinary team meeting. Combined operations such as biliary-intestinal anastomosis were applied when needed. Postoperative follow-up of all 184 patients was regularly performed according to institutional practice, including serum carbohydrate antigen 19-9 (CA19-9), α-fetoprotein (AFP), carcinoembryonic antigen (CEA), abdominal ultrasound, and chest X-ray every 3 months, and contrast-enhanced CT every 6 months. Recurrence was defined as the emergence of clinical, radiological, and/or pathological diagnosis (tissues obtained by ultrasound-guided fine-needle aspiration) of the tumor. Patients with confirmed recurrence of ICC received salvage treatments, such as repeated hepatectomy, percutaneous ablation or chemotherapy. DFS was calculated from the date of operation to the date of recurrence. OS was calculated from the date of operation to the date of death or last follow-up.

3. Statistical analysis

The best cut-off value of ANRI was determined by a receiver operating characteristic (ROC) curve. The difference between categorical variables was test by the Pearson chisquare test (two-tailed). Pearson bivariate correlate analyses (two-tailed) were used to compare the correlations of these categorical variables. Non-normally distributed numerical variables were tested using a Mann-Whitney U test. Survival curves (including stratified analysis) were plotted using the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazards model (Backward stepwise) was used to determine the independent prognostic factors based on variables selected on univariate analysis (with p < 0.05), and the results were expressed as a hazard ratio with a 95% confidence interval (95% CI). There are significant differences when p-values are < 0.05, using two-tailed tests. Statistical analyses performed using SPSS ver. 20.0 (IBM Corp., Armonk, NY).

Results

1. Demographic and clinicopathological characteristics

This study included 99 males (53.8%) and 85 females (46.2%). The mean age of the cohort was 56.0 years (range, 24 to 82 years). There were 163 patients (88.6%) who developed tumor recurrence and 152 patients (82.6%) died during the observation period. The mean tumor size was 6.0 cm (range, 1.0 to 20.0 cm) at the greatest diameter. Elevated serum CA19-9 (≥ 35.0 U/mL) was observed in 119 patients (64.7%), and 63 patients (34.2%) had multiple tumor masses. Serum hepatitis B surface antigen (HBsAg) was positive in 51 patients (27.7%), and cirrhosis existed in 46 patients (25.0%). Additionally, 28 patients had a past history of surgery due to hepatolithiasis. Tumor differentiation was defined according to the World Health Organization classification of tumors of the digestive system 2010 [10]. Tumors from 125 patients (67.9%) were well moderated, and those from 59 patients (32.1%) were poorly differentiated. In addition, 79 patients (42.9%) were in TNM stage I+II and 105 patients (57.1%) were in TNM stage III+IV (Table 1).

2. Determination of an ANRI cut-off value

ANRI was calculated using the formula: ANRI=(AST value/neutrophil count)×109/U. According to ROC curve analysis, the optimal cut-off value of ANRI was 6.7 for predicting postoperative prognosis. The area under ROC curve for survival status was 0.703, with a 95% CI of 0.604-0.802 (p < 0.001) (Fig. 1A). The maximal Youden Index (sensitivity+ specifcity–1) showed a sensitivity of 81.3% and a specificity of 57.9%. Subsequently, all patients were divided into two groups: a high ANRI group (> 6.7, n=90) and low ANRI group (≤ 6.7, n=94).

3. Relationship between ANRI and clinicopathological characteristics in ICC

The relationships between preoperative ANRI and clinicopathological variables were summarized in Table 1. The results showed that preoperative ANRI was related to tumor size (χ2=4.980, p=0.026), tumor recurrence (χ2=12.848, p < 0.001), white blood cell (χ2=21.971, p < 0.001), neutrophil count (χ2=26.679, p < 0.001), AST (χ2=48.122, p < 0.001), and alanine transaminase (χ2=18.952, p < 0.001). However, there were no significance associations of ANRI with age, sex, cirrhosis, HBsAg, tumor number, tumor differentiation, lymph node metastasis, vascular invasion, TNM stage, and CA19-9 (all p > 0.05) (Table 1).

4. Distribution of ANRI according to tumor size, recurrence, and lymph node metastasis

The results indicated that preoperative ANRI in ICC patients with a tumor size > 6 cm was markedly lower than those with a tumor size ≤ 6 cm (p=0.003) (Fig. 1B). This tendency also existed in ICC patients with tumor recurrence and lymph node metastasis, compared to those without tumor recurrence and lymph node metastasis (p=0.003 and p=0.026, respectively) (Fig. 1B).

5. Prognostic factors for ICC

In this study, the 1-year and 3-year OS rates of all patients were 37.0% and 13.0%, respectively. The 1-year and 3-year DFS rates were 22.3% and 11.3%, respectively. The median OS and DFS times were 10.0 and 4.0 months, respectively. Univariate analysis and the multivariate Cox’s proportional hazard regression model analysis were performed to identify the risk factors of prognosis. Univariate analysis revealed that preoperative ANRI (p=0.004), sex (p=0.014), tumor number (p=0.003), tumor size (p=0.006), tumor differentiation (p=0.002), TNM stage (p=0.002), resection margin (p=0.001), lymph node metastasis (p=0.003), neutrophil (p=0.034), and CEA (p=0.008) were prognostic factors for OS among the ICC cohort (Table 2). The preoperative ANRI (p=0.003), sex (p=0.035), tumor number (p=0.001), tumor size (p < 0.001), tumor differentiation (p=0.020), TNM stage (p=0.003), resection margin (p=0.001), lymph node metastasis (p=0.011), intraoperative blood loss (p=0.024), neutrophil (p=0.031), and CEA (p=0.001) were prognostic predictors for DFS in patients with ICC after hepatectomy (Table 2). After multivariate analysis, the results indicated that ANRI, tumor number, tumor size, tumor differentiation, and resection margin were significant independent prognostic markers of OS (all p < 0.05), while ANRI, tumor size, differentiation, and resection margin were independent predictors of DFS (all p < 0.05) (Table 3).

6. OS and DFS according to ANRI

Kaplan-Meier method was performed to clarify the influence of preoperative ANRI on patient survival. The results indicated that the 1-year and 3-year OS rates of the ANRI ≤ 6.7 group were markedly lower than those of the ANRI > 6.7 group (30.9% and 3.8% vs. 43.3% and 26.6%, respectively, p=0.004) (Table 2, Fig. 2A), while the 1-year and 3-year DFS rates of the ANRI ≤ 6.7 group were also significantly lower than those of the ANRI > 6.7 group (13.8% and 3.2% vs. 31.1% and 20.9%, respectively, p=0.003) (Table 2, Fig. 2B). Therefore, a low preoperative ANRI level was correlated with a poor survival outcome in patients with ICC after hepatectomy.

7. Prognostic values of ANRI in various subgroups of ICC

The research above confirmed that preoperative ANRI ≤ 6.7 was significantly correlated with lower OS and DFS rates in patients with ICC. We further evaluated the prognostic significance of preoperative ANRI in various subgroups of ICC patients. The data showed that preoperative ANRI was a prognostic predictor for OS (p=0.004) and DFS (p=0.004) in ICC patients with TNM stage of I+II (Fig. 3A and B). This predictive value of declined preoperative ANRI for poorer OS and DFS also existed in the subgroups of single tumor, without lymph node metastasis, R0 resection margin, without biliary-intestinal anastomosis, Child-Pugh Class A, serum HBsAg negative, AFP ≤ 200.0 μg/L, and CA19-9 > 35.0 U/mL (all p < 0.05) (Figs. 3C-F, 4, 5). These results suggested that preoperative ANRI was a sensitive parameter to predict the survival of ICC patients after hepatic resection, especially in various subgroups of patients with ICC whose prognosis is difficult to estimate.

Discussion

Tumor recurrence or metastasis severely influenced the prognosis of ICC after hepatectomy, a simple and effective method to identify surgical patients at high risk of recurrence is of great value for clinical work. In this study, we find ANRI to be a reliable non-invasive prognostic biomarker for ICC patients.
Inflammation and inflammatory biomarkers play a central role in tumor progression, associating with tumor proliferation, survival and migration [11]. Neutrophils are a critical component of the systemic inflammatory response and several studies have verified that the neutrophil count or neutrophil-lymphocyte ratio index were predictors of prognosis in various malignancies [7,12,13]. In the present study, we found that preoperative declined ANRI (≤ 6.7) showed earlier recurrence and poorer OS in ICC patients after hepatic resection. Additionally, our data suggested that ANRI was negatively related to tumor size and recurrence. These results indicated that ANRI could reflect not only the hepatocyte injury but also the tumor burden and disease development. Both univariate analysis and multivariate analysis showed that tumor size > 6 cm, poor differentiation, R1 resection margin and declined ANRI were independent risk factors for both poor OS and DFS of ICC patients after hepatectomy.
The results of further analysis showed that preoperative ANRI had a significant predictive value for both OS and DFS in ICC patients with TNM stage I+II, meaning that ANRI could predict recurrence of early ICC. As one of the risk factors of ICC, chronic hepatitis B virus infection impacted prognosis of ICC following resection [14]. It is usually more difficult to estimate the survival of serum HBsAg-negative patients. However, the data in this study indicated that ANRI shows its markedly prognostic value in those ICC patients. Furthermore, in subgroups with a single tumor, without lymph node metastasis, a R0 resection margin, without biliary-intestinal anastomosis, Child-Pugh Class A, an AFP ≤ 200.0 μg/L and an elevated CA19-9 level, preoperative ANRI ≤ 6.7 also shows its significance in predicting poorer OS and DFS.
These results showed that preoperative ANRI is a potential efficient prognostic indicator of survival in patients with ICC after hepatectomy. However, the exact reason for the association between declined preoperative ANRI and poor prognosis is not well understood. Our study showed that preoperative neutrophil count was markedly negatively correlated with ANRI, which means that patients with a lower ANRI have relative neutrophilia. The critical role of neutrophil in systemic inflammation and tumor progression might explain part of this phenomenon. Neutrophils were reported to facilitate tumor cell invasion and migration by secreting immune-reactive substances such as hepatocyte growth factor [15] and neutrophil elastase [16]. In addition, neutrophils can affect the prognosis of malignancy by directly down-regulating the cellular immunity function of the host [17]. ICC cells may recruit more neutrophils to the tumor foci by expressing higher levels of chemokine ligand 5, which amplifies the inflammatory response and promotes ICC metastasis and recurrence [18]. Furthermore, increased neutrophils are regarded as an important composition of compartments for circulating vascular endothelial growth factor (VEGF) [19]. Patients with lower ANRI have relative neutrophilia and may have a higher level of circulating VEGF. It has been reported that autocrine VEGF/vascular endothelial growth factor receptor 2 signaling promotes growth of ICC cells, and apatinib inhibits anti-apoptotic cell proliferation by suppressing the autocrine VEGF signaling [20]. Therefore, apatinib may be considered as a candidate in the treatment of ICC patients with lower preoperative ANRI.
There are some limitations in the present study. First, it is a retrospective study of a single center and the sample size is relatively small. Second, our data is mainly based on ICC patients with predominant hepatitis B virus infection and hepatolithiasis in China. Therefore, the results for application in Western populations with predominant primary sclerosing cholangitis [21] or hepatitis C virus infection should be further studied.
In conclusion, our study showed that preoperative declined ANRI is a novel independent indicator for poor prognosis of ICC patients after hepatectomy. ICC patients with preoperative declined ANRI might benefit from close follow up and prophylactic personalized therapy.

Conflicts of Interest

Conflict of interest relevant to this article was not reported.

Acknowledgments

This study was supported by the Research Fund of the Young Teacher Culture Program (Grant number: 15ykpy15) and the Natural Science Foundation of Guangdong Province (Grant number: 2014A030313108).

Fig. 1.
Receiver operating characteristic (ROC) curve and distribution of preoperative aspartate aminotransferase/neutrophil count ratio index (ANRI) in different intrahepatic cholangiocarcinoma (ICC) subgroups. (A) ROC analysis was performed to determine the optimal cut-off value of ANRI in patients with ICC after hepatectomy (cut-off value=6.7). The area under the ROC curve for survival status was 0.703 (95% confidence interval, 0.604 to 0.802; p < 0.001), with a sensitivity of 81.3% and a specificity of 57.9%. (B) Comparison of preoperative ANRI in ICC subgroups, stratified by tumor size, recurrence, and lymph node metastasis (LNM). The proportions of ICC patients with declined preoperative ANRI along with tumor size > 6 cm, recurrence, and with LNM are much higher than those with tumor size ≤ 6 cm, without recurrence, and without LNM, respectively (all p < 0.05, Mann-Whitney U test). AUC, area under the curve.
crt-2017-106f1.tif
Fig. 2.
Kaplan-Meier survival curves of overall survival (A) and disease-free survival (B) for intrahepatic cholangiocarcinoma patients with aspartate aminotransferase/neutrophil count ratio index (ANRI) > 6.7 and ANRI ≤ 6.7 in the entire cohort. p-values were obtained by log-rank tests.
crt-2017-106f2.tif
Fig. 3.
Kaplan-Meier survival curves of patients with intrahepatic cholangiocarcinoma after hepatectomy stratified by TNM stage I+II (A, B), single tumor status (C, D), and without lymph node metastasis (E, F). p-values were obtained by log-rank tests. ANRI, aspartate aminotransferase/neutrophil count ratio index.
crt-2017-106f3.tif
Fig. 4.
Kaplan-Meier survival curves of patients with intrahepatic cholangiocarcinoma after hepatectomy stratified by R0 resection margin (A, B), without biliary-intestinal anastomosis (C, D), and Child-Pugh Class A (E, F). p-values were obtained by log-rank tests. ANRI, aspartate aminotransferase/ neutrophil count ratio index.
crt-2017-106f4.tif
Fig. 5.
Kaplan-Meier survival curves of patients with intrahepatic cholangiocarcinoma after hepatectomy stratified by serum hepatitis B surface antigen (HBsAg) negative (A, B), α-fetoprotein (AFP) ≤ 200.0 μg/L (C, D), and carbohydrate antigen 19-9 (CA19-9) > 35.0 U/mL (E, F). p-values were obtained by log-rank tests. ANRI, aspartate aminotransferase/neutrophil count ratio index.
crt-2017-106f5.tif
Table 1.
Relationship between ANRI and clinicopathological characteristics in ICC (n=184)
Category No. ANRI
χ2 r p-value
≤ 6.7 (n=94) > 6.7 (n=90)
Age (yr)
 ≤ 60 117 59 (50.4) 58 (49.6) 0.056 - 0.813
 > 60 67 35 (52.2) 32 (47.8)
Sex
 Female 85 40 (47.1) 45 (52.9) 1.026 - 0.311
 Male 99 54 (54.5) 45 (45.5)
Preoperative symptom
 No 51 26 (51.0) 25 (49.0) 0.000 - 0.986
 Yes 133 68 (51.1) 65 (48.9)
Cirrhosis
No 138 70 (50.7) 68 (49.3) 0.029 - 0.865
 Yes 46 24 (52.2) 22 (47.8)
HBsAg
 Negative 133 67 (50.4) 66 (49.6) 0.097 - 0.755
 Positive 51 27 (52.9) 24 (47.1)
Tumor number
 Single 121 60 (49.6) 61 (50.4) 0.318 - 0.573
 Multiple 63 34 (54.0) 29 (46.0)
Tumor size (cm)a)
 ≤ 6 97 42 (43.3) 55 (56.7) 4.980 –0.165 0.026
 > 6 87 52 (59.8) 35 (40.2)
Capsulation
 No 111 58 (52.3) 53 (47.7) 0.152 - 0.697
 Yes 73 36 (49.3) 37 (50.7)
Differentiationb)
 W+M 125 60 (48.0) 65 (52.0) 1.487 - 0.223
 P 59 34 (57.6) 25 (42.4)
Lymph node metastasis
 No 111 51 (45.9) 60 (54.1) 2.959 - 0.085
 Yes 73 43 (58.9) 30 (41.1)
Vascular invasion
 No 174 90 (52.0) 83 (48.0) 1.015 - 0.314
 Yes 11 4 (36.4) 7 (63.6)
TNMc)
 I+II 79 39 (49.4) 40 (50.6) 0.164 - 0.686
 III+IV 105 55 (52.4) 50 (47.6)
Resection margin
 R0 108 60 (55.6) 48 (44.4) 2.089 - 0.148
 R1 76 34 (44.7) 42 (55.3)
Biliary-intestinal anastomosis
 No 158 83 (52.5) 75 (47.5) 0.934 - 0.334
 Yes 26 11 (42.3) 15 (57.7)
Complication
 No 155 79 (51.0) 76 (49.0) 0.006 - 0.940
 Yes 29 15 (51.7) 14 (48.3)
Intraoperative blood loss (mL)a)
 ≤ 400 104 55 (52.9) 49 (47.1) 0.309 - 0.578
 > 400 80 39 (48.8) 41 (51.2)
Recurrence
 No 21 3 (14.3) 18 (85.7) 12.848 –0.264 < 0.001
 Yes 163 91 (55.8) 72 (44.2)
WBC (×109/L)
 ≤ 10 148 63 (42.6) 85 (57.4) 21.971 –0.346 < 0.001
 > 10 36 31 (86.1) 5 (13.9)
Neutrophil (×109/L)a)
 ≤ 4.55 93 30 (32.3) 63 (67.7) 26.679 –0.381 < 0.001
 > 4.55 91 64 (70.3) 27 (29.7)
Platelet (×109/L)
 ≤ 300 139 66 (47.5) 73 (52.5) 2.956 - 0.086
 > 300 45 28 (62.2) 17 (37.8)
AST (U/L)
 ≤ 37 133 89 (66.9) 44 (33.1) 48.122 0.511 < 0.001
 > 37 51 5 (9.8) 46 (90.2)
ALT (U/L)
 ≤ 80 158 91 (57.6) 67 (42.4) 18.952 0.321 < 0.001
 > 80 26 3 (11.5) 23 (88.5)
γ-GT (U/L)
 ≤ 50 50 24 (48.0) 26 (52.0) 0.262 - 0.609
 > 50 134 70 (52.2) 64 (47.8)
AFP (μg/L)
 ≤ 200 176 89 (50.6) 87 (49.4) 0.436 - 0.509
 > 200 8 5 (62.5) 3 (37.5)
CEA (μg/L)
 ≤ 5.0 107 53 (49.5) 54 (50.5) 0.247 - 0.619
 > 5.0 77 41 (53.2) 36 (46.8)
CA19-9 (U/mL)
 ≤ 35 65 37 (56.9) 28 (43.1) 1.370 - 0.242
 > 35 119 57 (47.9) 62 (52.1)

ANRI, aspartate aminotransferase/neutrophil count ratio index; ICC, intrahepatic cholangiocarcinoma; HBsAg, hepatitis B surface antigen; W+M, well+moderated differentiation; P, poor differentiation; WBC, white blood cell; AST, aspartate aminotransferase; ALT, alanine transaminase; γ-GT, γ-glutamyl transpeptidase; AFP, α-fetoprotein; CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19-9.

a) Medians were used for cut-off values,

b) According to the World Health Organization (WHO) classification of tumors of the digestive system 2010,

c) Based on seventh edition cancer staging manual of American Joint Committee on Cancer.

Table 2.
Univariate analyses for prognostic factors of patients with ICC (n=184)
Category No. OS
p-value DFS
p-value
1-Year (%) 3-Year (%) 1-Year (%) 3-Year (%)
Age (yr)
 ≤ 60 117 34.2 13.4 0.723 20.5 10.9 0.437
 > 60 67 41.8 11.2 25.4 11.9
Sex
 Female 85 47.1 15.6 0.014 30.6 14.6 0.035
 Male 99 28.3 8.1 15.2 8.5
Preoperative symptom
 No 51 41.2 16.7 0.464 27.5 10.5 0.575
 Yes 133 35.3 10.1 20.3 11.4
Cirrhosis
 No 138 39.1 12.6 0.303 23.9 11.7 0.268
 Yes 46 30.4 8.6 17.4 9.9
HBsAg
 Negative 133 36.8 13.1 0.916 23.3 11.9 0.465
 Positive 51 37.3 9.5 19.6 9.8
Child-Pugh class
 A 164 36.0 11.3 0.272 20.7 9.5 0.148
 B 20 45.0 25.0 35.0 16.7
No. of tumors
 Single 121 43.0 15.3 0.003 28.1 13.8 0.001
 Multiple 63 25.4 5.5 11.1 6.3
Tumor size (cm)a)
 ≤ 6 97 46.4 17.6 0.006 33.0 16.2 < 0.001
 > 6 87 26.4 7.9 10.3 5.7
Tumor differentiation
 Well+moderated 125 42.4 16.4 0.002 25.6 13.20 0.02
 Poor 59 25.4 6.1 15.3 7.60
Capsulation
 Noncapsulated 111 35.1 8.4 0.206 21.6 9.30 0.647
 Capsulated 73 39.7 17.7 23.3 14.10
Vascular invasion
 No 173 38.2 13.6 0.112 22.5 12.10 0.114
 Yes 11 18.2 0.0 18.2 0.0
TNM
 I+II 79 46.8 18.2 0.002 32.9 19.6 0.003
 III+IV 105 29.5 6.1 14.3 5.3
Resection margin
 R0 108 42.6 20.1 0.001 28.7 17.0 0.001
 R1 76 28.9 0.0 13.2 2.60
Lymph node metastasis
 No 111 43.2 17.7 0.003 29.7 15.5 0.011
 Yes 73 27.4 3.9 11.0 5.1
Biliary-intestinal anastomosis
 No 158 38.0 13.0 0.504 23.4 11.2 0.607
 Yes 26 30.8 13.5 15.4 11.5
Complication
 No 155 38.1 12.8 0.389 23.9 11.8 0.127
 Yes 29 31.0 23.0 13.8 9.2
Intraoperative blood loss (mL)a)
 ≤ 400 104 42.3 13.5 0.068 25.0 12.4 0.024
 > 400 80 30.0 12.1 18.7 10.0
WBC (×109/L)
 ≤ 10 148 39.2 13.9 0.214 24.3 11.9 0.088
 > 10 36 27.8 10.0 13.9 8.3
Neutrophil (×109/L)a)
 ≤ 4.55 93 44.1 17.1 0.034 28.0 13.7 0.031
 > 4.55 91 29.7 9.1 16.5 8.8
Platelet (×109/L)
 ≤ 300 139 37.4 13.0 0.754 22.3 11.0 0.963
 > 300 45 35.6 14.7 22.2 12.3
AST (U/L)
 ≤ 37 133 36.1 8.9 0.284 21.1 7.6 0.425
 > 37 51 39.2 20.3 25.5 16.3
ALT (U/L)
 ≤ 80 158 36.7 9.8 0.083 20.3 8.5 0.092
 > 80 26 38.5 34.6 34.6 26.9
γ-GT (U/L)
 ≤ 50 50 48.0 12.3 0.275 28.0 9.9 0.292
 > 50 134 32.8 13.5 20.1 10.1
AFP (μg/L)
 ≤ 200 176 36.9 13.1 0.658 22.7 11.2 0.259
 > 200 8 37.5 0.0 12.5 0.0
CEA (μg/L)
 ≤ 5 107 44.9 17.7 0.008 29.9 13.4 0.001
 > 5 77 26.0 6.6 11.7 5.5
CA19-9 (U/mL)
 ≤ 35 65 43.1 12.0 0.324 24.6 8.3 0.554
 > 35 119 33.6 13.9 21.0 11.2
ANRI
 ≤ 6.7 94 30.9 3.8 0.004 13.8 3.2 0.003
 > 6.7 90 43.3 26.6 31.1 20.9

ICC, intrahepatic cholangiocarcinoma; OS, overall survival; DFS, disease-free survival; HBsAg, hepatitis B surface antigen; WBC, white blood cell; AST, aspartate aminotransferase; ALT, alanine transaminase; γ-GT, γ-glutamyl transpeptidase; AFP, α-fetoprotein; CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19-9; ANRI, aspartate aminotransferase/neutrophil count ratio index.

a) Medians were used for cut-off values.

Table 3.
Multivariate analyses for independent prognostic factors of patients with ICC (n=184)
Category OS
DFS
HR (95% CI) p-value HR (95% CI) p-value
Tumor number (single vs. multiple) 1.473 (1.048-2.069) 0.026 - -
Tumor size (≤ 6 cm vs. > 6 cm) 1.408 (1.013-1.959) 0.042 1.725 (1.251-2.380) 0.001
Tumor differentiation (W+M vs. P) 1.687 (1.202-2.366) 0.002 1.501 (1.078-2.090) 0.016
Resection margin (R0 vs. R1) 0.556 (0.401-0.770) < 0.001 0.580 (0.421-0.800) 0.001
ANRI (> 6.7 vs. ≤ 6.7) 0.671 (0.482-0.934) 0.018 0.664 (0.483-0.911) 0.011

Variables with p < 0.05 calculated by Kaplan-Meier method (log-rank test) were used in multivariate analysis (Cox proportional hazards model, Backward stepwise). ICC, intrahepatic cholangiocarcinoma; OS, overall survival; DFS, disease-free survival; HR, hazard ratio; CI, confidence interval; W+M, well+moderated differentiation; P, poor differentiation; ANRI, aspartate aminotransferase/neutrophil count ratio index.

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